Red blood cell (RBC) products for transfusion undergo metabolic and physical changes during storage characterized as RBC storage lesions that may result in extravascular hemolysis and inflammation, vasoconstriction, and potentially compromised oxygenation upon transfusion. To address this defect, we have proposed the rational design and development of HemoDefend, a hemocompatible, highly porous polymer bead optimized to broadly remove contaminants such as free hemoglobin, potassium, reactive antibodies, bioactive lipids, inflammatory cytokines, reactive proteins and microvesicles from stored pRBCs based on a proven pore capture and surface adsorption technology platform. These hemocompatible beads would be assessed in two configurations: 1) Beads-in-a-Bag, and 2) a dockable, in-line filter. In the first approach, the beads will be placed directly into the blood bag to adsorb blood contaminants during the storage period. In the second approach, the beads would be contained in a small in-line cartridge placed between the blood bag and the patient. After identifying optimal polymer sorbents, we will evaluate each test configuration for the ability to remove 11 contaminants and inflammatory mediators from pRBC units. Given the extended direct contact with erythrocytes, we will specifically evaluate seven parameters to assess hemocompatibility of the bead candidates. We will also evaluate whether HemoDefend treatment can prevent some of the deleterious morphological changes that occur to stored RBCs using image capture and differential cell counting. The outcome will be the demonstration of a powerful and easy-to-use blood purification technology to maintain and potentially improve the quality and safety of stored blood.